The important role of VEGF-A in pathological and non-pathological angiogenesis is well established. Administration of VEGF in in vivo models induces a potent angiogenic response (Plouet, J et al., (1989) EMBO J. 8:3801-3808; Leung, D. W., et al., (1989) Science 246:1306-1309). Loss of a single VEGF-A allele gave rise to an embryonic lethality in mice (Carmeliet, P., et al., (1996) Nature 380:435-439; Ferrara, N et al., (1996) Nature 380:439-442). VEGF is also known as a vascular permeability factor due to its ability to induce vascular leakage (Senger, D. R. et al., (1995) Science 219:983-985; Dvorak, H. F., et al., (1995) Am. J. Pathol. 146:1029-1039). Thus, VEGF-A is involved in the developmental, reproductive and bone angiogenesis in addition to other non-pathological angiogenesis.
VEGF-A binds to two receptor tyrosine kinases (RTK), VEGFR-1 (Flt-1) and VEGFR-2 (KDR, Flk-1). VEGFR-2 is generally thought to be the major mediator of the mitogenic, angiogenic and permeability-enhancing effects of VEGF-A. In February 2004, the US Food and Drug Administration (FDA) approved bevacizumab, a humanized anti-VEGF (vascular endothelial growth factor)-A monoclonal antibody, for the treatment of metastatic colorectal cancer in combination with 5-fluorouracil (FU)-based chemotherapy regimens. Subsequently, the FDA approved pegaptinib, an aptamer that blocks the 165 amino-acid isoform of VEGF-A, for the treatment of the wet (neovascular) form of age-related macular degeneration (AMD).
Despite these advances, many patients treated with VEGF antagonists eventually succumb to their disease. Consequently there exists a need to develop new medicaments and treatments for treating diseases that are no longer responsive or are only partially responsive to VEGF antagonist therapies. There also exist a need to develop alternative and/or better therapies for treating cancer and diseases worsened, caused by or effected by abnormal angiogenesis.